The polyomavirus JCV has infected greater than 70% of us and persists in most of our kidneys. JCV also causes PML, a fatal brain disease that is now killing 2-4% of AIDS patients. The strain of JCV circulating in the population (via urine) appears to differ from that found in PML brain. PML has been thought to arise as the result of a reactivation of a latent kidney infection. During this event, alterations to the viral genome may generate a more active variant capable of infecting oligodendrocytes and causing demyelination of the brain. Results from several labs support this adaptation model and indicate that one type of JCV, called archetype, predominates in the urine of immunodeficient individuals. After prolonged immunosuppression, new strains of JCV are detected that differ from archetype by deletion and duplication of sequences within the promoter-enhancer region. Our long-term objective is to define the balance between viral latency and pathogenicity. With this knowledge should come the ability to control and prevent the fatal disease PML. Successful completion of the proposed studies will represent a major step towards accomplishing our goal. Questions addressed by the 4 specific aims include: Aim 1. Can PCR analysis be used to confirm and extend the surprising finding that JCV is present in the brains of most "normal,, individuals? Can this method detect JCV in, cerebral spinal fluid for early diagnosis of PML and in fetal tissue to uncover transplacental transmission? Is JCV associated with human medulloblastomas? Aim 2. Using PCR analysis, in situ hybridization and immunocytochemistry, can the site of persistence and multiplication of JCV in the kidney be identified? Which kidney cells support JCV growth in culture? Aim 3. Can in vivo adaptation of JCV be observed before/after renal transplantation? How do the brain and archetype strains of JCV differ phenotypically? Will archetype be expressed and cause disease in transgenic mice? What factors allow HIV-1 to reactivate a latent JCV infection, and does a similar interaction occur in SIV-infected monkeys? Aim 4. What role does the interaction between the JCV T antigen and the cellular anti-oncogene-products Rb and p53 play in latency and the restricted transforming behavior of this DNA tumor virus?